Approximately 8% of the human genome is composed of integrated copies of retroviral DNA. At least some of the endogenous retroviruses are transcribed and translated into proteins, but the functional consequences are unclear. Nevertheless, endogenous retroviruses encode many of the same genes as exogenous retroviruses, which are known to manipulate the immune system to allow chronic infections and disease. For example, endogenous proviruses related to the betaretrovirus mouse mammary tumor virus (MMTV) (aka Mtvs) are known to affect the T-cell repertoire of mice through expression of superantigen (Sag). A novel mouse strain, BALB/Mtv-null, has been developed that is congenic to BALB/c mice, but lacks endogenous Mtv proviruses. We have shown that the Mtv-null mice are more resistant to specific viral and bacterial pathogens, including exogenous MMTV, Friend murine leukemia virus, and the gram- negative bacterium, Vibrio cholerae, compared to the parental BALB/c strain. Although the mechanism of resistance may not be the same for each pathogen, preliminary data indicate that Mtv-null mice have increased numbers of mature invariant natural killer T (iNKT) cells compared to those of BALB/c mice. Interestingly, individual Mtv proviruses, which are located on different mouse chromosomes and have different numbers of genes, do not contribute equally to iNKT phenotype or resistance to pathogen infection. Susceptibility to V. cholerae is reconstituted by any one of three endogenous Mtvs, including one that encodes only Sag. Nevertheless, the Sag-only Mtv provirus only partially reconstitutes susceptibility to MMTV-induced mammary tumors, and does not increase susceptibility to Friend virus disease. On the other hand, a complete provirus, Mtv9, reconstitutes susceptibility to both MMTV and Friend virus. Complete MMTV proviruses encode Rem, a Rev-like protein related to the human endogenous virus type K (HERV-K) Rec protein. Rec has been shown to interact with the transcription factor, PLZF, which controls the function and maturation of iNKT cells. We propose that Rev-like proteins encoded by specific murine and human retroviruses control the immune response to pathogens through PLZF and iNKT cells. In the first specific aim, transgenic mice expressing either rem or rec will be developed and characterized for their effects on the maturation of iNKT cells and susceptibility to exogenous retroviruses. In the second specific aim, primary thymocytes will be transduced with retroviruses expressing either rem or rec to determine their effects on cellular phenotype and PLZF function. These experiments will increase our understanding of T- cell selection and differentiation as well as the immune response to pathogens. The long-term goal of this proposal is the development of new approaches for treatment of infectious disease.